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Showing papers by "University of Alabama at Birmingham published in 2016"


Journal ArticleDOI
Daniel J. Klionsky1, Kotb Abdelmohsen2, Akihisa Abe3, Joynal Abedin4  +2519 moreInstitutions (695)
TL;DR: In this paper, the authors present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macro-autophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes.
Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure flux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation, it is imperative to target by gene knockout or RNA interference more than one autophagy-related protein. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways implying that not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular assays, we hope to encourage technical innovation in the field.

5,187 citations


Journal ArticleDOI
Theo Vos1, Christine Allen1, Megha Arora1, Ryan M Barber1  +696 moreInstitutions (260)
TL;DR: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) as discussed by the authors was used to estimate the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015.

5,050 citations


Journal ArticleDOI
Haidong Wang1, Mohsen Naghavi1, Christine Allen1, Ryan M Barber1  +841 moreInstitutions (293)
TL;DR: The Global Burden of Disease 2015 Study provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015, finding several countries in sub-Saharan Africa had very large gains in life expectancy, rebounding from an era of exceedingly high loss of life due to HIV/AIDS.

4,804 citations


Journal ArticleDOI
TL;DR: IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
Abstract: It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

2,367 citations


Journal ArticleDOI
21 Jun 2016-JAMA
TL;DR: It is concluded with high certainty that screening for colorectal cancer in average-risk, asymptomatic adults aged 50 to 75 years is of substantial net benefit.
Abstract: Importance Colorectal cancer is the second leading cause of cancer death in the United States. In 2016, an estimated 134 000 persons will be diagnosed with the disease, and about 49 000 will die from it. Colorectal cancer is most frequently diagnosed among adults aged 65 to 74 years; the median age at death from colorectal cancer is 73 years. Objective To update the 2008 US Preventive Services Task Force (USPSTF) recommendation on screening for colorectal cancer. Evidence Review The USPSTF reviewed the evidence on the effectiveness of screening with colonoscopy, flexible sigmoidoscopy, computed tomography colonography, the guaiac-based fecal occult blood test, the fecal immunochemical test, the multitargeted stool DNA test, and the methylated SEPT9 DNA test in reducing the incidence of and mortality from colorectal cancer or all-cause mortality; the harms of these screening tests; and the test performance characteristics of these tests for detecting adenomatous polyps, advanced adenomas based on size, or both, as well as colorectal cancer. The USPSTF also commissioned a comparative modeling study to provide information on optimal starting and stopping ages and screening intervals across the different available screening methods. Findings The USPSTF concludes with high certainty that screening for colorectal cancer in average-risk, asymptomatic adults aged 50 to 75 years is of substantial net benefit. Multiple screening strategies are available to choose from, with different levels of evidence to support their effectiveness, as well as unique advantages and limitations, although there are no empirical data to demonstrate that any of the reviewed strategies provide a greater net benefit. Screening for colorectal cancer is a substantially underused preventive health strategy in the United States. Conclusions and Recommendations The USPSTF recommends screening for colorectal cancer starting at age 50 years and continuing until age 75 years (A recommendation). The decision to screen for colorectal cancer in adults aged 76 to 85 years should be an individual one, taking into account the patient’s overall health and prior screening history (C recommendation).

2,100 citations


Journal ArticleDOI
TL;DR: To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA), a large number of patients with RA are referred to a single clinic for treatment with these medications.
Abstract: Objective To develop a new evidence-based, pharmacologic treatment guideline for rheumatoid arthritis (RA). Methods We conducted systematic reviews to synthesize the evidence for the benefits and harms of various treatment options. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence. We employed a group consensus process to grade the strength of recommendations (either strong or conditional). A strong recommendation indicates that clinicians are certain that the benefits of an intervention far outweigh the harms (or vice versa). A conditional recommendation denotes uncertainty over the balance of benefits and harms and/or more significant variability in patient values and preferences. Results The guideline covers the use of traditional disease-modifying antirheumatic drugs (DMARDs), biologic agents, tofacitinib, and glucocorticoids in early (<6 months) and established (≥6 months) RA. In addition, it provides recommendations on using a treat-to-target approach, tapering and discontinuing medications, and the use of biologic agents and DMARDs in patients with hepatitis, congestive heart failure, malignancy, and serious infections. The guideline addresses the use of vaccines in patients starting/receiving DMARDs or biologic agents, screening for tuberculosis in patients starting/receiving biologic agents or tofacitinib, and laboratory monitoring for traditional DMARDs. The guideline includes 74 recommendations: 23% are strong and 77% are conditional. Conclusion This RA guideline should serve as a tool for clinicians and patients (our two target audiences) for pharmacologic treatment decisions in commonly encountered clinical situations. These recommendations are not prescriptive, and the treatment decisions should be made by physicians and patients through a shared decision-making process taking into account patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

2,083 citations


Journal ArticleDOI
01 Apr 2016
TL;DR: ASD prevalence estimates for children aged 8 years living in catchment areas of the ADDM Network sites in 2012 are provided, overall and stratified by sex, race/ethnicity, and the type of source records (education and health records versus health records only).
Abstract: PROBLEM/CONDITION Autism spectrum disorder (ASD). PERIOD COVERED 2012. DESCRIPTION OF SYSTEM The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance system that provides estimates of the prevalence and characteristics of ASD among children aged 8 years whose parents or guardians reside in 11 ADDM Network sites in the United States (Arkansas, Arizona, Colorado, Georgia, Maryland, Missouri, New Jersey, North Carolina, South Carolina, Utah, and Wisconsin). Surveillance to determine ASD case status is conducted in two phases. The first phase consists of screening and abstracting comprehensive evaluations performed by professional service providers in the community. Data sources identified for record review are categorized as either 1) education source type, including developmental evaluations to determine eligibility for special education services or 2) health care source type, including diagnostic and developmental evaluations. The second phase involves the review of all abstracted evaluations by trained clinicians to determine ASD surveillance case status. A child meets the surveillance case definition for ASD if one or more comprehensive evaluations of that child completed by a qualified professional describes behaviors that are consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision diagnostic criteria for any of the following conditions: autistic disorder, pervasive developmental disorder-not otherwise specified (including atypical autism), or Asperger disorder. This report provides ASD prevalence estimates for children aged 8 years living in catchment areas of the ADDM Network sites in 2012, overall and stratified by sex, race/ethnicity, and the type of source records (education and health records versus health records only). In addition, this report describes the proportion of children with ASD with a score consistent with intellectual disability on a standardized intellectual ability test, the age at which the earliest known comprehensive evaluation was performed, the proportion of children with a previous ASD diagnosis, the specific type of ASD diagnosis, and any special education eligibility classification. RESULTS For 2012, the combined estimated prevalence of ASD among the 11 ADDM Network sites was 14.5 per 1,000 (one in 69) children aged 8 years. Estimated prevalence was significantly higher among boys aged 8 years (23.4 per 1,000) than among girls aged 8 years (5.2 per 1,000). Estimated ASD prevalence was significantly higher among non-Hispanic white children aged 8 years (15.3 per 1,000) compared with non-Hispanic black children (13.1 per 1,000), and Hispanic (10.2 per 1,000) children aged 8 years. Estimated prevalence varied widely among the 11 ADDM Network sites, ranging from 8.2 per 1,000 children aged 8 years (in the area of the Maryland site where only health care records were reviewed) to 24.6 per 1,000 children aged 8 years (in New Jersey, where both education and health care records were reviewed). Estimated prevalence was higher in surveillance sites where education records and health records were reviewed compared with sites where health records only were reviewed (17.1 per 1,000 and 10.4 per 1,000 children aged 8 years, respectively; p<0.05). Among children identified with ASD by the ADDM Network, 82% had a previous ASD diagnosis or educational classification; this did not vary by sex or between non-Hispanic white and non-Hispanic black children. A lower percentage of Hispanic children (78%) had a previous ASD diagnosis or classification compared with non-Hispanic white children (82%) and with non-Hispanic black children (84%). The median age at earliest known comprehensive evaluation was 40 months, and 43% of children had received an earliest known comprehensive evaluation by age 36 months. The percentage of children with an earliest known comprehensive evaluation by age 36 months was similar for boys and girls, but was higher for non-Hispanic white children (45%) compared with non-Hispanic black children (40%) and Hispanic children (39%). INTERPRETATION Overall estimated ASD prevalence was 14.5 per 1,000 children aged 8 years in the ADDM Network sites in 2012. The higher estimated prevalence among sites that reviewed both education and health records suggests the role of special education systems in providing comprehensive evaluations and services to children with developmental disabilities. Disparities by race/ethnicity in estimated ASD prevalence, particularly for Hispanic children, as well as disparities in the age of earliest comprehensive evaluation and presence of a previous ASD diagnosis or classification, suggest that access to treatment and services might be lacking or delayed for some children. PUBLIC HEALTH ACTION The ADDM Network will continue to monitor the prevalence and characteristics of ASD among children aged 8 years living in selected sites across the United States. Recommendations from the ADDM Network include enhancing strategies to 1) lower the age of first evaluation of ASD by community providers in accordance with the Healthy People 2020 goal that children with ASD are evaluated by age 36 months and begin receiving community-based support and services by age 48 months; 2) reduce disparities by race/ethnicity in identified ASD prevalence, the age of first comprehensive evaluation, and presence of a previous ASD diagnosis or classification; and 3) assess the effect on ASD prevalence of the revised ASD diagnostic criteria published in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.

1,553 citations


Journal ArticleDOI
Nicholas J Kassebaum1, Megha Arora1, Ryan M Barber1, Zulfiqar A Bhutta2  +679 moreInstitutions (268)
TL;DR: In this paper, the authors used the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015) for all-cause mortality, cause-specific mortality, and non-fatal disease burden to derive HALE and DALYs by sex for 195 countries and territories from 1990 to 2015.

1,533 citations


Journal ArticleDOI
TL;DR: The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts, and therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.
Abstract: In adult mammals, massive sudden loss of cardiomyocytes after infarction overwhelms the limited regenerative capacity of the myocardium, resulting in the formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of proinflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/ chemokine (C-C motif) ligand 2 [CCL2]). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin–angiotensin–aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response after myocardial infarction. Dysregulation of immune pathways, impaired suppression of postinfarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for the prevention of postinfarction heart failure.

1,266 citations


Journal ArticleDOI
TL;DR: IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
Abstract: It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

1,124 citations


Journal ArticleDOI
TL;DR: Analysis of whole-exome sequencing data of metastatic biopsies from patients observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas and neuroendocrine prostate cancer (CRPC-NE), supporting the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.
Abstract: An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, in which tumor cells demonstrate low to absent AR expression and often have neuroendocrine features. The etiology and molecular basis for this 'alternative' treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.

Journal ArticleDOI
TL;DR: The results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
Abstract: Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.

Journal ArticleDOI
TL;DR: This review summarizes the recent advances in the understanding of TGF-β/BMP signaling in osteoblast differentiation, chondrocyte differentiation, skeletal development, cartilage formation, bone formation,Bone homeostasis, and related human bone diseases caused by the disruption of T GF-β / BMP signaling.
Abstract: Transforming growth factor-beta (TGF-β) and bone morphogenic protein (BMP) signaling has fundamental roles in both embryonic skeletal development and postnatal bone homeostasis. TGF-βs and BMPs, acting on a tetrameric receptor complex, transduce signals to both the canonical Smad-dependent signaling pathway (that is, TGF-β/BMP ligands, receptors, and Smads) and the non-canonical-Smad-independent signaling pathway (that is, p38 mitogen-activated protein kinase/p38 MAPK) to regulate mesenchymal stem cell differentiation during skeletal development, bone formation and bone homeostasis. Both the Smad and p38 MAPK signaling pathways converge at transcription factors, for example, Runx2 to promote osteoblast differentiation and chondrocyte differentiation from mesenchymal precursor cells. TGF-β and BMP signaling is controlled by multiple factors, including the ubiquitin-proteasome system, epigenetic factors, and microRNA. Dysregulated TGF-β and BMP signaling result in a number of bone disorders in humans. Knockout or mutation of TGF-β and BMP signaling-related genes in mice leads to bone abnormalities of varying severity, which enable a better understanding of TGF-β/BMP signaling in bone and the signaling networks underlying osteoblast differentiation and bone formation. There is also crosstalk between TGF-β/BMP signaling and several critical cytokines' signaling pathways (for example, Wnt, Hedgehog, Notch, PTHrP, and FGF) to coordinate osteogenesis, skeletal development, and bone homeostasis. This review summarizes the recent advances in our understanding of TGF-β/BMP signaling in osteoblast differentiation, chondrocyte differentiation, skeletal development, cartilage formation, bone formation, bone homeostasis, and related human bone diseases caused by the disruption of TGF-β/BMP signaling.

Journal ArticleDOI
TL;DR: The final recommendations recognize that obesity is a complex, adiposity-based chronic disease, where management targets both weight-related complications and adiposity to improve overall health and quality of life.

Journal ArticleDOI
28 Jun 2016-JAMA
TL;DR: Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBp target of more than 140mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause.
Abstract: Importance The appropriate treatment target for systolic blood pressure (SBP) in older patients with hypertension remains uncertain. Objective To evaluate the effects of intensive ( Design, Setting, and Participants A multicenter, randomized clinical trial of patients aged 75 years or older who participated in the Systolic Blood Pressure Intervention Trial (SPRINT). Recruitment began on October 20, 2010, and follow-up ended on August 20, 2015. Interventions Participants were randomized to an SBP target of less than 120 mm Hg (intensive treatment group, n = 1317) or an SBP target of less than 140 mm Hg (standard treatment group, n = 1319). Main Outcomes and Measures The primary cardiovascular disease outcome was a composite of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure, and death from cardiovascular causes. All-cause mortality was a secondary outcome. Results Among 2636 participants (mean age, 79.9 years; 37.9% women), 2510 (95.2%) provided complete follow-up data. At a median follow-up of 3.14 years, there was a significantly lower rate of the primary composite outcome (102 events in the intensive treatment group vs 148 events in the standard treatment group; hazard ratio [HR], 0.66 [95% CI, 0.51-0.85]) and all-cause mortality (73 deaths vs 107 deaths, respectively; HR, 0.67 [95% CI, 0.49-0.91]). The overall rate of serious adverse events was not different between treatment groups (48.4% in the intensive treatment group vs 48.3% in the standard treatment group; HR, 0.99 [95% CI, 0.89-1.11]). Absolute rates of hypotension were 2.4% in the intensive treatment group vs 1.4% in the standard treatment group (HR, 1.71 [95% CI, 0.97-3.09]), 3.0% vs 2.4%, respectively, for syncope (HR, 1.23 [95% CI, 0.76-2.00]), 4.0% vs 2.7% for electrolyte abnormalities (HR, 1.51 [95% CI, 0.99-2.33]), 5.5% vs 4.0% for acute kidney injury (HR, 1.41 [95% CI, 0.98-2.04]), and 4.9% vs 5.5% for injurious falls (HR, 0.91 [95% CI, 0.65-1.29]). Conclusions and Relevance Among ambulatory adults aged 75 years or older, treating to an SBP target of less than 120 mm Hg compared with an SBP target of less than 140 mm Hg resulted in significantly lower rates of fatal and nonfatal major cardiovascular events and death from any cause. Trial Registration clinicaltrials.gov Identifier:NCT01206062

Journal ArticleDOI
TL;DR: The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria for placental lesions, which will assist in international comparability of clinicopathologic and scientific studies and assist in refining the significance of lesions associated with adverse pregnancy and later health outcomes.
Abstract: Context.—The value of placental examination in investigations of adverse pregnancy outcomes may be compromised by sampling and definition differences between laboratories. Objective.—To establish an agreed-upon protocol for sampling the placenta, and for diagnostic criteria for placental lesions. Recommendations would cover reporting placentas in tertiary centers as well as in community hospitals and district general hospitals, and are also relevant to the scientific research community. Data Sources.—Areas of controversy or uncertainty were explored prior to a 1-day meeting where placental and perinatal pathologists, and maternal-fetal medicine specialists discussed available evidence and subsequently reached consensus where possible. Conclusions.—The group agreed on sets of uniform sampling criteria, placental gross descriptors, pathologic terminologies, and diagnostic criteria. The terminology and microscopic descriptions for maternal vascular malperfusion, fetal vascular malperfusion, delayed villous m...

Journal ArticleDOI
TL;DR: Issues from grading of acne to the topical and systemic management of the disease are reviewed and suggestions on use are provided based on available evidence.
Abstract: Acne is one of the most common disorders treated by dermatologists and other health care providers. While it most often affects adolescents, it is not uncommon in adults and can also be seen in children. This evidence-based guideline addresses important clinical questions that arise in its management. Issues from grading of acne to the topical and systemic management of the disease are reviewed. Suggestions on use are provided based on available evidence.

Journal ArticleDOI
TL;DR: This portion of the NCCN Guidelines discusses general principles for the diagnosis, staging, and treatment of STS of the extremities, superficial trunk, or head and neck; outlines treatment recommendations by disease stage; and reviews the evidence to support the guidelines recommendations.
Abstract: Soft tissue sarcomas (STS) are rare solid tumors of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Guidelines for STS provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as intra-abdominal/retroperitoneal STS, gastrointestinal stromal tumors, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis, staging, and treatment of STS of the extremities, superficial trunk, or head and neck; outlines treatment recommendations by disease stage; and reviews the evidence to support the guidelines recommendations.

Journal ArticleDOI
Juanita A. Haagsma1, Nicholas Graetz1, Ian Bolliger1, Mohsen Naghavi1, Hideki Higashi1, Erin C Mullany1, Semaw Ferede Abera2, Jerry Puthenpurakal Abraham3, Koranteng Adofo4, Ubai Alsharif5, Emmanuel A. Ameh6, Walid Ammar, Carl Abelardo T. Antonio7, Lope H Barrero8, Tolesa Bekele9, Dipan Bose10, Alexandra Brazinova, Ferrán Catalá-López, Lalit Dandona1, Rakhi Dandona11, Paul I. Dargan12, Diego De Leo13, Louisa Degenhardt14, Sarah Derrett15, Samath D Dharmaratne16, Tim Driscoll17, Leilei Duan18, Sergey Petrovich Ermakov19, Farshad Farzadfar20, Valery L. Feigin21, Richard C. Franklin22, Belinda J. Gabbe23, Richard A. Gosselin24, Nima Hafezi-Nejad20, Randah R. Hamadeh25, Martha Híjar, Guoqing Hu26, Sudha Jayaraman27, Guohong Jiang, Yousef Khader28, Ejaz Ahmad Khan29, Sanjay Krishnaswami30, Chanda Kulkarni, Fiona Lecky31, Ricky Leung32, Raimundas Lunevicius33, Ronan A Lyons34, Marek Majdan, Amanda J. Mason-Jones35, Richard Matzopoulos36, Peter A. Meaney37, Wubegzier Mekonnen38, Ted R. Miller39, Charles Mock40, Rosana E. Norman41, Ricardo Orozco, Suzanne Polinder, Farshad Pourmalek42, Vafa Rahimi-Movaghar20, Amany H. Refaat43, David Rojas-Rueda, Nobhojit Roy44, David C. Schwebel45, Amira Shaheen46, Saeid Shahraz47, Vegard Skirbekk48, Kjetil Søreide49, Sergey Soshnikov, Dan J. Stein50, Bryan L. Sykes51, Karen M. Tabb52, Awoke Misganaw Temesgen, Eric Y. Tenkorang53, Alice Theadom21, Bach Xuan Tran54, Bach Xuan Tran55, Tommi Vasankari, Monica S. Vavilala40, Vasiliy Victorovich Vlassov56, Solomon Meseret Woldeyohannes57, Paul S. F. Yip58, Naohiro Yonemoto, Mustafa Z. Younis59, Chuanhua Yu60, Christopher J L Murray1, Theo Vos1 
Institute for Health Metrics and Evaluation1, College of Health Sciences, Bahrain2, Harvard University3, Kwame Nkrumah University of Science and Technology4, Charité5, Ahmadu Bello University6, University of the Philippines Manila7, Pontifical Xavierian University8, Madawalabu University9, World Bank10, Public Health Foundation of India11, Guy's and St Thomas' NHS Foundation Trust12, Griffith University13, University of New South Wales14, Massey University15, University of Peradeniya16, University of Sydney17, Chinese Center for Disease Control and Prevention18, Russian Academy of Sciences19, Tehran University of Medical Sciences20, Auckland University of Technology21, James Cook University22, Monash University23, University of California, San Francisco24, Arabian Gulf University25, Central South University26, Virginia Commonwealth University27, Jordan University of Science and Technology28, Health Services Academy29, Oregon Health & Science University30, University of Sheffield31, University at Albany, SUNY32, Aintree University Hospitals NHS Foundation Trust33, Swansea University34, University of York35, South African Medical Research Council36, Children's Hospital of Philadelphia37, Addis Ababa University38, Curtin University39, University of Washington40, Queensland University of Technology41, University of British Columbia42, Suez Canal University43, Karolinska Institutet44, University of Alabama at Birmingham45, An-Najah National University46, Tufts Medical Center47, Norwegian Institute of Public Health48, Stavanger University Hospital49, University of Cape Town50, University of California, Irvine51, University of Illinois at Urbana–Champaign52, St. John's University53, Hanoi Medical University54, Johns Hopkins University55, National Research University – Higher School of Economics56, University of Gondar57, University of Hong Kong58, Jackson State University59, Wuhan University60
TL;DR: An overview of injury estimates from the 2013 update of GBD is provided, with detailed information on incidence, mortality, DALYs and rates of change from 1990 to 2013 for 26 causes of injury, globally, by region and by country.
Abstract: Background The Global Burden of Diseases (GBD), Injuries, and Risk Factors study used the disability-adjusted life year (DALY) to quantify the burden of diseases, injuries, and risk factors. This paper provides an overview of injury estimates from the 2013 update of GBD, with detailed information on incidence, mortality, DALYs and rates of change from 1990 to 2013 for 26 causes of injury, globally, by region and by country. Methods Injury mortality was estimated using the extensive GBD mortality database, corrections for ill-defined cause of death and the cause of death ensemble modelling tool. Morbidity estimation was based on inpatient and outpatient data sets, 26 cause-of-injury and 47 nature-of-injury categories, and seven follow-up studies with patient-reported long-term outcome measures. Results In 2013, 973 million (uncertainty interval (UI) 942 to 993) people sustained injuries that warranted some type of healthcare and 4.8 million (UI 4.5 to 5.1) people died from injuries. Between 1990 and 2013 the global age-standardised injury DALY rate decreased by 31% (UI 26% to 35%). The rate of decline in DALY rates was significant for 22 cause-of-injury categories, including all the major injuries. Conclusions Injuries continue to be an important cause of morbidity and mortality in the developed and developing world. The decline in rates for almost all injuries is so prominent that it warrants a general statement that the world is becoming a safer place to live in. However, the patterns vary widely by cause, age, sex, region and time and there are still large improvements that need to be made.

Journal ArticleDOI
TL;DR: To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA), a large number of patients with RA are referred to a single clinic for treatment with these medications.
Abstract: To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA).

Journal ArticleDOI
22 Nov 2016-JAMA
TL;DR: Palliative care was associated consistently with improvements in advance care planning, patient and caregiver satisfaction, and lower health care utilization, and evidence of associations with other outcomes was mixed.
Abstract: Importance The use of palliative care programs and the number of trials assessing their effectiveness have increased. Objective To determine the association of palliative care with quality of life (QOL), symptom burden, survival, and other outcomes for people with life-limiting illness and for their caregivers. Data Sources MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL to July 2016. Study Selection Randomized clinical trials of palliative care interventions in adults with life-limiting illness. Data Extraction and Synthesis Two reviewers independently extracted data. Narrative synthesis was conducted for all trials. Quality of life, symptom burden, and survival were analyzed using random-effects meta-analysis, with estimates of QOL translated to units of the Functional Assessment of Chronic Illness Therapy–palliative care scale (FACIT-Pal) instrument (range, 0-184 [worst-best]; minimal clinically important difference [MCID], 9 points); and symptom burden translated to the Edmonton Symptom Assessment Scale (ESAS) (range, 0-90 [best-worst]; MCID, 5.7 points). Main Outcomes and Measures Quality of life, symptom burden, survival, mood, advance care planning, site of death, health care satisfaction, resource utilization, and health care expenditures. Results Forty-three RCTs provided data on 12 731 patients (mean age, 67 years) and 2479 caregivers. Thirty-five trials used usual care as the control, and 14 took place in the ambulatory setting. In the meta-analysis, palliative care was associated with statistically and clinically significant improvements in patient QOL at the 1- to 3-month follow-up (standardized mean difference, 0.46; 95% CI, 0.08 to 0.83; FACIT-Pal mean difference, 11.36] and symptom burden at the 1- to 3-month follow-up (standardized mean difference, −0.66; 95% CI, −1.25 to −0.07; ESAS mean difference, −10.30). When analyses were limited to trials at low risk of bias (n = 5), the association between palliative care and QOL was attenuated but remained statistically significant (standardized mean difference, 0.20; 95% CI, 0.06 to 0.34; FACIT-Pal mean difference, 4.94), whereas the association with symptom burden was not statistically significant (standardized mean difference, −0.21; 95% CI, −0.42 to 0.00; ESAS mean difference, −3.28). There was no association between palliative care and survival (hazard ratio, 0.90; 95% CI, 0.69 to 1.17). Palliative care was associated consistently with improvements in advance care planning, patient and caregiver satisfaction, and lower health care utilization. Evidence of associations with other outcomes was mixed. Conclusions and Relevance In this meta-analysis, palliative care interventions were associated with improvements in patient QOL and symptom burden. Findings for caregiver outcomes were inconsistent. However, many associations were no longer significant when limited to trials at low risk of bias, and there was no significant association between palliative care and survival.

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TL;DR: This chapter discusses the development and use of eicosapentaenoic acid as a treatment for diabetic ketoacidosis and its applications in conventional and regenerative medicine.

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12 Jul 2016-JAMA
TL;DR: In this article, the authors provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis.
Abstract: Importance New data and therapeutic options warrant updated recommendations for the use of antiretroviral drugs (ARVs) to treat or to prevent HIV infection in adults. Objective To provide updated recommendations for the use of antiretroviral therapy in adults (aged ≥18 years) with established HIV infection, including when to start treatment, initial regimens, and changing regimens, along with recommendations for using ARVs for preventing HIV among those at risk, including preexposure and postexposure prophylaxis. Evidence Review A panel of experts in HIV research and patient care convened by the International Antiviral Society–USA reviewed data published in peer-reviewed journals, presented by regulatory agencies, or presented as conference abstracts at peer-reviewed scientific conferences since the 2014 report, for new data or evidence that would change previous recommendations or their ratings. Comprehensive literature searches were conducted in the PubMed and EMBASE databases through April 2016. Recommendations were by consensus, and each recommendation was rated by strength and quality of the evidence. Findings Newer data support the widely accepted recommendation that antiretroviral therapy should be started in all individuals with HIV infection with detectable viremia regardless of CD4 cell count. Recommended optimal initial regimens for most patients are 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus an integrase strand transfer inhibitor (InSTI). Other effective regimens include nonnucleoside reverse transcriptase inhibitors or boosted protease inhibitors with 2 NRTIs. Recommendations for special populations and in the settings of opportunistic infections and concomitant conditions are provided. Reasons for switching therapy include convenience, tolerability, simplification, anticipation of potential new drug interactions, pregnancy or plans for pregnancy, elimination of food restrictions, virologic failure, or drug toxicities. Laboratory assessments are recommended before treatment, and monitoring during treatment is recommended to assess response, adverse effects, and adherence. Approaches are recommended to improve linkage to and retention in care are provided. Daily tenofovir disoproxil fumarate/emtricitabine is recommended for use as preexposure prophylaxis to prevent HIV infection in persons at high risk. When indicated, postexposure prophylaxis should be started as soon as possible after exposure. Conclusions and Relevance Antiretroviral agents remain the cornerstone of HIV treatment and prevention. All HIV-infected individuals with detectable plasma virus should receive treatment with recommended initial regimens consisting of an InSTI plus 2 NRTIs. Preexposure prophylaxis should be considered as part of an HIV prevention strategy for at-risk individuals. When used effectively, currently available ARVs can sustain HIV suppression and can prevent new HIV infection. With these treatment regimens, survival rates among HIV-infected adults who are retained in care can approach those of uninfected adults.

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University of Utah1, University of Colorado Boulder2, Stanford University3, Oregon Health & Science University4, University of Chicago5, Rush University Medical Center6, University of Barcelona7, Harvard University8, Vanderbilt University9, University of Arizona10, University of Texas Health Science Center at Houston11, University of Pennsylvania12, Emory University13, Université de Montréal14, Samsung Medical Center15, University of Auckland16, University of Pittsburgh17, University of Amsterdam18, University of Ioannina19, University of California, San Francisco20, Eastern Virginia Medical School21, University of New South Wales22, Katholieke Universiteit Leuven23, Guy's and St Thomas' NHS Foundation Trust24, University of Lorraine25, University of British Columbia26, Northwestern University27, Georgia Regents University28, Johns Hopkins University29, New York University30, Korea University31, University of Texas at Austin32, Uniformed Services University of the Health Sciences33, Jikei University School of Medicine34, University of Washington35, University of Siena36, Medical College of Wisconsin37, University of Adelaide38, West Virginia University39, Innsbruck Medical University40, Pusan National University41, University of Calgary42, Medical University of South Carolina43, University of North Carolina at Chapel Hill44, Cleveland Clinic45, Loyola University Chicago46, Cornell University47, Temple University48, University of São Paulo49, National University of Singapore50, San Antonio Military Medical Center51, University of Alabama at Birmingham52, University of Alberta53, Capital Medical University54
TL;DR: This dissertation aims to provide a history of Chinese medical practice in the United States from 1989 to 2002, a period chosen in order to explore its roots as well as specific cases up to and including the year in which descriptions of “modern China” began to circulate.
Abstract: Background The body of knowledge regarding rhinosinusitis(RS) continues to expand, with rapid growth in number of publications, yet substantial variability in the quality of those presentations. In an effort to both consolidate and critically appraise this information, rhinologic experts from around the world have produced the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS). Methods Evidence-based reviews with recommendations(EBRRs) were developed for scores of topics, using previously reported methodology. Where existing evidence was insufficient for an EBRR, an evidence-based review (EBR)was produced. The sections were then synthesized and the entire manuscript was then reviewed by all authors for consensus. Results The resulting ICAR:RS document addresses multiple topics in RS, including acute RS (ARS), chronic RS (CRS)with and without nasal polyps (CRSwNP and CRSsNP), recurrent acute RS (RARS), acute exacerbation of CRS (AECRS), and pediatric RS. Conclusion As a critical review of the RS literature, ICAR:RS provides a thorough review of pathophysiology and evidence-based recommendations for medical and surgical treatment. It also demonstrates the significant gaps in our understanding of the pathophysiology and optimal management of RS. Too often the foundation upon which these recommendations are based is comprised of lower level evidence. It is our hope that this summary of the evidence in RS will point out where additional research efforts may be directed.

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TL;DR: In this article, the authors quantified maternal mortality throughout the world by underlying cause and age from 1990 to 2015 for ages 10-54 years by systematically compiling and processing all available data sources from 186 of 195 countries and territories.

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TL;DR: This report of initial and durable responses of recurrent GBM to immune checkpoint inhibition may have implications for GBM in general and other hypermutant cancers arising from primary (genetic predisposition) or secondary MMRD.
Abstract: PurposeRecurrent glioblastoma multiforme (GBM) is incurable with current therapies. Biallelic mismatch repair deficiency (bMMRD) is a highly penetrant childhood cancer syndrome often resulting in GBM characterized by a high mutational burden. Evidence suggests that high mutation and neoantigen loads are associated with response to immune checkpoint inhibition.Patients and MethodsWe performed exome sequencing and neoantigen prediction on 37 bMMRD cancers and compared them with childhood and adult brain neoplasms. Neoantigen prediction bMMRD GBM was compared with responsive adult cancers from multiple tissues. Two siblings with recurrent multifocal bMMRD GBM were treated with the immune checkpoint inhibitor nivolumab.ResultsAll malignant tumors (n = 32) were hypermutant. Although bMMRD brain tumors had the highest mutational load because of secondary polymerase mutations (mean, 17,740 ± standard deviation, 7,703), all other high-grade tumors were hypermutant (mean, 1,589 ± standard deviation, 1,043), simila...

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Roby Joehanes, Allan C. Just1, Riccardo E. Marioni2, Luke C. Pilling1, Lindsay M. Reynolds1, Pooja R. Mandaviya3, Weihua Guan, Tao Xu2, Cathy E. Elks2, Stella Aslibekyan1, Hortensia Moreno-Macías4, Jennifer A. Smith3, Jennifer A. Brody3, Radhika Dhingra3, Paul Yousefi5, James S. Pankow, Sonja Kunze, Sonia Shah6, Allan F. McRae6, Kurt Lohman6, Jin Sha7, Jin Sha8, Devin Absher8, Luigi Ferrucci8, Wei Zhao9, Ellen W. Demerath7, Jan Bressler6, Megan L. Grove8, Tianxiao Huan9, Tianxiao Huan10, Chunyu Liu5, Chunyu Liu3, Chunyu Liu2, Michael M. Mendelson, Chen Yao1, Douglas P. Kiel4, Annette Peters11, Rui Wang-Sattler, Peter M. Visscher12, Naomi R. Wray, John M. Starr13, Jingzhong Ding3, Carlos J. Rodriguez1, Nicholas J. Wareham, Marguerite R. Irvin2, Degui Zhi2, Myrto Barrdahl2, Paolo Vineis1, Srikant Ambatipudi, André G. Uitterlinden2, Albert Hofman14, Joel Schwartz10, Elena Colicino15, Lifang Hou3, Pantel S. Vokonas2, D. Hernandez16, Andrew B. Singleton, Stefania Bandinelli17, Stephen Turner, Erin B. Ware, Alicia K. Smith, Torsten Klengel18, Elisabeth B. Binder19, Bruce M. Psaty20, Kent D. Taylor, Sina A. Gharib1, Brenton R. Swenson21, Liming Liang22, Dawn L. DeMeo, George T. O'Connor, Zdenko Herceg1, Kerry J. Ressler23, Karen N. Conneely11, N. Sotoodehnia24, Sharon L.R. Kardia2, David Melzer17, Andrea A. Baccarelli1, Joyce B. J. van Meurs1, Isabelle Romieu3, Donna K. Arnett, Ken K. Ong, Yongmei Liu19, M. Waldenberger25, Ian J. Deary1, Myriam Fornage26, Daniel Levy, Stephanie J. London11 
TL;DR: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years aftersmoking cessation, indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation.
Abstract: Background —DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. Methods and Results —To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15,907 blood derived DNA samples from participants in 16 cohorts (including 2,433 current, 6,518 former, and 6,956 never smokers). Comparing current versus never smokers, 2,623 CpG sites (CpGs), annotated to 1,405 genes, were statistically significantly differentially methylated at Bonferroni threshold of p<1×10-7 (18,760 CpGs at False Discovery Rate (FDR)<0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant p<1×10-7 (2,623 CpGs at FDR<0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. Conclusions —Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biologic effects of smoking, and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.

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TL;DR: The results support the use of isavuconazole for the primary treatment of patients with invasive mould disease and non-inferiority was shown.

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TL;DR: There have been considerable changes in care for mothers in preterm labor and for extremely preterm infants since the 1990s, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network has monitored changes.
Abstract: Obstet Gynecol Surv 2016;71(1):7–9Since the 1990s, there have been considerable changes in care for mothers in preterm labor and for extremely preterm infants. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network has monitored changes in this

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Haidong Wang1, Zulfiqar A Bhutta2, Zulfiqar A Bhutta3, Matthew M Coates1  +610 moreInstitutions (263)
TL;DR: The Global Burden of Disease 2015 Study provides an analytical framework to comprehensively assess trends for under-5 mortality, age-specific and cause-specific mortality among children under 5 years, and stillbirths by geography over time and decomposed the changes in under- 5 mortality to changes in SDI at the global level.